4AL0: Crystal Structure of Human Ps-1

Citation:
Abstract
Prostaglandin E (PGE) is a key mediator in inflammatory response. The main source of inducible PGE, microsomal PGE synthase-1 (mPGES-1), has emerged as an interesting drug target for treatment of pain. To support inhibitor design, we have determined the crystal structure of human mPGES-1 to 1.2 A resolution. The structure reveals three well-defined active site cavities within the membrane-spanning region in each monomer interface of the trimeric structure. An important determinant of the active site cavity is a small cytosolic domain inserted between transmembrane helices I and II. This extra domain is not observed in other structures of proteins within the MAPEG (Membrane-Associated Proteins involved in Eicosanoid and Glutathione metabolism) superfamily but is likely to be present also in microsomal GST-1 based on sequence similarity. An unexpected feature of the structure is a 16-A-deep cone-shaped cavity extending from the cytosolic side into the membrane-spanning region. We suggest a potential role for this cavity in substrate access. Based on the structure of the active site, we propose a catalytic mechanism in which serine 127 plays a key role. We have also determined the structure of mPGES-1 in complex with a glutathione-based analog, providing insight into mPGES-1 flexibility and potential for structure-based drug design.
PDB ID: 4AL0Download
MMDB ID: 107266
PDB Deposition Date: 2012/2/29
Updated in MMDB: 2013/03 
Experimental Method:
x-ray diffraction
Resolution: 1.16  Å
Source Organism:
Similar Structures:
Biological Unit for 4AL0: trimeric; determined by author and by software (PISA)
Molecular Components in 4AL0
Label Count Molecule
Proteins (3 molecules)
3
Prostaglandin E Synthase(Gene symbol: PTGES)
Molecule annotation
Chemicals (18 molecules)
1
3
2
9
3
6
* Click molecule labels to explore molecular sequence information.

Citing MMDB
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